DESCRIPTION: This application proposes an investigation of the mechanisms of coronary vasodilation. Vasodilation is generally associated with a decrease in smooth muscle cytoplasmic Ca2+ levels. Therefore, it is critical to understand the mechanisms which lead to the closing of voltage dependent Ca2+ channels and consequently a reduction in the entry of Ca2+ into the cell. The overall hypothesis for the present studies is that voltage dependent Ca2+ channels are modulated both directly by vasodilators as well as indirectly via the changes in membrane potential which accompany the opening of K+ channels. Further, it is proposed that the specific nature of these effects differs significantly between vasodilators. To investigate this hypothesis experiments are proposed using the patch clamp technique on isolated smooth muscle cells to characterize the actions of vasodilators on both K+ channels and voltage dependent Ca2+ channels. To relate these channel effects to the actions of vasodilators in the intact tissue, membrane potential and relaxation of isolated ring segments of coronary artery (+/- endothelium) will be measured. The vasodilator pathways which will be investigated in this application include: 1) adenosine and cAMP, 2) nitric oxide and cGMP, 3) endothelium derived hyperpolarizing factor "EDHF", 4) ATP and 5) the K+ channel opener lemakalim. The overall objective of this work is to understand how these physiologically relevant vasodilators modulate K+ and Ca2+ channel activity and thus better understand how coronary arterial tone is regulated.